Matrix metalloproteinases (MMPs) are a family of structurally related zinc-dependent proteolytic enzymes that digest extracellular matrix proteins such as collagen, elastin, laminin and fibronectin. Currently, at least 28 different mammalian MMP proteins have been identified, and are grouped based on substrate specificity and domain structure. The wide variety of MMPs normally participate in many different homeostatic tissue remodeling events. Given this broad functional diversity it is not surprising that MMP dysfunction would give rise to a host of different pathologies. A role for MMPs in oncology has been the most extensively explored, as up-regulation of any number of MMPs are one mechanism by which malignant cells can overcome connective tissue barriers and metastasize (Curr Cancer Drug Targets 5: 203-20 (2005)). MMPs also appear to have a direct role in angiogenesis, also making them an important target for oncology indications (Int J Cancer 115: 849-60 (2005) and J Cell Mol Med 9: 267-85 (2005)). Several different classes of MMPs are involved in these processes, but MMP-2, -9 and MT1-MMP have been most often implicated. The cartilage and bone degeneration that results in osteoarthritis and rheumatoid arthritis is due primarily to MMP digestion of the ECM in bone and joints (Aging Clin Exp Res 15: 364-72 (2003). MMP-1, -2, -9, and -13 have been found to be elevated in the tissues and body fluids surrounding damaged tissues. MMPs also have a role in cardiovascular diseases in that they are believed to be involved in atherosclerotic plaque rupture, aneurysm and vascular and myocardial tissue morphogenesis (Expert Opin Investig Drugs 9: 993-1007 (2000) and Curr Med Chem 12: 917-25 (2005)). Elevated levels of MMP-1, -2, -9, and -13 have often been associated with these conditions. Several other pathologies such as gastric ulcers, pulmonary hypertension, chronic obstructive pulmonary disease, inflammatory bowel disease, periodontal disease, skin ulcers, liver fibrosis, emphysema, and Marfan's syndrome appear to involve MMP as well (Expert Opin Ther Patents 12: 665-707 (2002)).
Two enzymes, MMP-2 and MMP-9, appear to have the most significant impact in propagating the brain tissue damage that occurs following an ischemic or hemorrhagic insult. Studies in stroke patients and in animal stroke models have demonstrated that both MMP-2 and -9 expression levels and activity increase sharply over a 24 hour period following an ischemic event. Within the brain, the microvascular endothelial cell tight-junctions are broken down by activated MMP-2 and -9, which results in increased permeability of the blood-brain barrier (BBB). This breakdown in the integrity of the BBB then leads to edema and infiltration of inflammatory agents, both of which cause increased cell death around the infarct core (the penumbra) and increase the possibility of hemorrhagic transformation. Administration of MMP inhibitors has shown to be protective in animal models of stroke (Stroke 29: 1020-30 (1998); Expert Opin Investig Drugs 8: 255-68 (1999); Stroke 31: 3034-40 (2000); Stroke 34: 2025-30 (2003); and J Neurosci 25: 6401-8 (2005)). MMP-9 knockout animals also demonstrate significant neuroprotection in similar stroke models (J Cereb Blood Flow Metab 20: 1681-9 (2000)). In the U.S., stroke is the leading cause of disability, and the third leading cause of mortality. Currently, thrombolitics (e.g. t-PA) are the only approved therapy for stroke; however its use is severely limited due to a narrow dosing window of time and potential hemorrhagic risk. This area has a large unmet medical need for acute interventional therapy.
MMP-9 has also been suggested to play a role in the progression of multiple sclerosis (MS). Studies have indicated that serum levels of MMP-9 are elevated in active patients, and are concentrated around MS lesions (Lancet Neurol 2: 747-56 (2003)). Increased serum MMP-9 activity would promote infiltration of leukocytes into the CNS, a causal factor and one of the hallmarks of the disease. MMPs may also contribute to the severity and prolongation of migraines. In animal models of migraine (cortical spreading depression), MMP-9 is rapidly upregulated and activated leading to a breakdown in the BBB, which results in mild to moderate edema (J Clin Invest 113: 1447-55 (2004)). It is this brain swelling and subsequent vasoconstriction that causes the debilitating headaches and other symptoms associated with migraine. In the cortical spreading depression model, MMP inhibitors have been shown to prevent the opening of the BBB (J Clin Invest 113: 1447-55 (2004)). Related research has shown that MMP-9 is specifically upregulated in damaged brain tissues following traumatic brain injury (J Neurotrauma 19: 615-25 (2002)), which would be predicted to lead to further brain damage due to edema and immune cell infiltration.
Within the central nervous system, altered MMP expression has been linked to several neurodegenerative and neurovascular disease states (Expert Opin Investig Drugs 8: 255-68 (1999)), most notably in stroke (Glia 50: 329-39 (2005)). MMPs may also have additional roles in other chronic CNS disorders. In an animal model of Parkinson's disease, MMP-9 was found to be rapidly upregulated after striatal injection of a dopaminergic neuron poison (MPTP) (Neuromolecular Med 5: 119-32 (2004)), and MMP-3 has been shown to process α-synuclein to an aggregation-prone form (J Biol Chem 280: 25216-24 (2005)). This implicates MMPs in both the neuronal remodeling that occurs upon cell loss and one of the potential causative factors of the disease. In patients with Alzheimer's disease, MMP-9 was found to be upregulated in postmortem plasma samples compared to normal controls (Expert Opin Investig Drugs 8: 255-68 (1999) and Neurochem Int 43: 191-6 (2003)). Furthermore, pathologic expression of Aβ peptides induces expression and activation of MMP-2, which may contribute to cerebral amyloid angiopathy, a major pathological feature of Alzheimer's disease (J Neurochem 85: 1208-15 (2003)). MMPs may also have a role in vascular dementia, as MMP-9 levels have been found to be elevated in the cerebrospinal fluid from demented patients (Stroke 35: e159-62 (2004)). Clearly, the pathologic expression of various MMPs can contribute to many different neurodegenerative disorders.
A wide range of MMP inhibitors (MMPIs) have been discussed comprehensively in several review articles (Whittaker, M. et al Chem. Rev. 1999, 99, 2735-2776; Skiles, J W. et al Curr. Med. Chem. 2001, 8, 425-474; Skiles, J W. et al Curr. Med. Chem. 2004, 11, 2911-2977; Matter, H. et al Curr. Opin. In Drug Discov. & Dev. 2004, 7, 513-535). A classical approach to the MMPI design is the combination of a zinc-binding group (ZBG) and a side chain binding to enzymes. The most common ZBGs used in MMPI design are hydroxamates, N-hydroxy-formamides, thiols, carboxylates and phosphonic acids. Some of MMPIs incorporating these “classical” ZBGs have been developed for pharmaceutical uses but failed in clinical trials.
A considerable effort was put on discovery of non-classical ZBG based MMPIs and several MMPIs with heterocyclic ZBGs have been disclosed: barbiturates (WO 2005/0107414); thiadiazole derivatives (Protein Sci. 1998, 7, 2281-2286; Bioorg. Med. Chem. Lett. 2002, 12, 2667-2672); thiadiazine compounds (J. Med. Chem. 2001, 44, 3231-3243; EP-01191024 (2001)); imidazolidinedione derivatives (WO 2004/024718 A1; WO 2002/07475148-WO2002/07475152); triazolones (WO 2005/095362 A1).
In JP-02105073 (2002), Shionogi & Co discloses a class of hydroxyl- and alkoxy-succimide with sulfonamide scaffolds as MMP inhibitors stated to have the generic structure
wherein the substituents are as described in the reference.
Eriksson et al. disclose in WO 03/040098 certain metalloproteinase inhibitors stated to have the structure
wherein the substituents are as described in the reference.
A galardin (GM 6001) analog with a six-membered ring as ZBG is reported to show weak MMP inhibitory activity on all MMPs tested with IC50's ranging from 20.1 to 104 μM (Chinese J. Chem., 2001, 19, 286), which compound is shown below:

Cohen et al report a bioinorganic approach to MMP inhibition (Curr. Top. In Med Chem. 2004, 4, 1551; J. Am. Chem. Soc. 2004, 126, 8388-8389). A tris-His active site model of MMP suggests a group of hydroxyl-pyridones (HOPO) and hydroxyl-pyranones, structures of which are shown below, may serve as cyclic six-membered zinc binding functionality. Some of these heterocyclic compounds have been used in siderophore synthesis as Fe(III) chelators and in the synthesis of Pu(IV) sequestering agents.

The HOPOs exhibit activity ranging from several hundred to several thousand micromolar for inhibiting MMP3. It is stated that hydroxy-thiopyridones and -thiopyranones are several tens fold more potent than their oxygen-analogs due to zinc thiophilicity.
A series of MMP inhibitors incorporating a pyrone moiety as ZBG has been reported (J. Am. Chem. Soc. 2005, 127, 14148-14149). The best compound shows around 10 nM of IC50 against MMP-3 and 0.61 μM against MMP-2. The general structure is shown below, wherein P1′ group was assembled next to the hydroxyl group on the pyrone ring.

We have now discovered a series of novel compounds incorporating a variety of from six- to nine-membered heterocycle ZBGs useful as MMP inhibitors. The compounds of this invention are potent MMP-2, -9 and -13 inhibitors, while exhibiting less activity against MMP-1. In addition, the compounds of this invention may selectively inhibit other MMPs.